Background The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

https://spiral.imperial.ac.uk/bitstream/10044/1/74273/2/Glucagon-like%20peptide%201%20%28GLP-1%29%20Molecular%20Metabolism.pdf

Glucagon-like peptide 1 (GLP-1)

In healthy humans, the incretin glucagon-like peptide 1 (GLP-1) is secreted after eating and lowers glucose concentrations by augmenting insulin secretion and suppressing glucagon release. Additional effects of GLP-1 include retardation of gastric emptying, suppression of appetite and, potentially, inhibition of β-cell apoptosis. Native GLP-1 is degraded within ~2-3 min in the circulation; various GLP-1 receptor agonists have, therefore, been developed to provide prolonged in vivo actions. These GLP-1 receptor agonists can be categorized as either short-acting compounds, which provide short-lived receptor activation (such as exenatide and lixisenatide) or as long-acting compounds (for example albiglutide, dulaglutide, exenatide long-acting release, and liraglutide), which activate the GLP-1 receptor continuously at their recommended dose. The pharmacokinetic differences between these drugs lead to important differences in their pharmacodynamic profiles. The short-acting GLP-1 receptor agonists primarily lower postprandial blood glucose levels through inhibition of gastric emptying, whereas the long-acting compounds have a stronger effect on fasting glucose levels, which is mediated predominantly through their insulinotropic and glucagonostatic actions. The adverse effect profiles of these compounds also differ. The individual properties of the various GLP-1 receptor agonists might enable incretin-based treatment of type 2 diabetes mellitus to be tailored to the needs of each patient.

GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.

http://csmres.co.uk/cs.public.upd/article-downloads/Future-directions-for-peptide-therapeutics-development.pdf

Future directions for peptide therapeutics development.

Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to min...

Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide

Protein and peptide therapeutics require parenteral administration, which can be a deterrent to medication adherence. For this reason, there have been extensive efforts to develop alternative delivery strategies, particularly for peptides such as insulin that are used to treat endocrine disorders. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. It then focuses on the experience with oral peptides that have reached clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin, with an emphasis on the advances that have recently led to the landmark approval of an oral formulation of the glucagon-like peptide 1 receptor agonist semaglutide for the treatment of type 2 diabetes.

Advances in oral peptide therapeutics.

Background
Glucagon-like peptide-1 (GLP-1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose-dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight-reducing profile. However, a short half-life (minutes), secondary to rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native GLP-1 hormone. Recently, the GLP-1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long-acting and efficacious GLP-1 analogues represents a pivotal research goal. We developed a GLP-1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods
In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results
LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half-life in rats and cynomolgus monkeys was 1.5–2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose-dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions
LY2189265 retains the effects of GLP-1 with increased half-life and efficacy, supporting further evaluation as a once-weekly treatment of type 2 diabetes. Copyright © 2010 John Wiley & Sons, Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/dmrr.1080

Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein.

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Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein.